基于网络药理学及分子对接和基因芯片验证右美托咪定治疗脑缺血再灌注损伤的作用机制

Verification of the mechanism of action of dexmedetomidine in treatment of cerebral ischemia-reperfusion injury based on network pharmacology,molecular docking,and gene chip analysis

目的基于生物信息学分析右美托咪定治疗脑缺血再灌注损伤的作用机制,结合分子对接和基因表达综合库(GEO)芯片验证明确核心基因。方法采用PubChem和GeneCards筛选右美托咪定和脑缺血再灌注损伤交集靶点,建立蛋白相互作用(PPI)网络确定Hub基因,进行基因本体(GO)和京都基因与基因组百科全书(KEGG)富集分析,最终采用分子对接和GEO芯片数据验证Hub基因。结果右美托咪定和脑缺血再灌注损伤有43个交集靶点,PPI筛选得到41个节点和103条边的拓扑网络,Hub基因为5-羟色胺受体2A(HTR2A)、阿片受体mu 1(OPRM1)、多巴胺受体D2(DRD2)、溶质载体家族6成员4(SLC6A4)、谷氨酸代谢型受体5(GRM5)、细胞色素P450家族2亚家族C成员19(CYP2C19)、溶质载体家族6成员3(SLC6A3)、核受体亚家族3C组成员1(NR3C1)、糖原合成酶激酶3β(GSK3β)。GO和KEGG分析显示右美托咪定干预脑缺血再灌注损伤涉及254种生物学功能和58条信号通路。分子对接验证Hub基因均具有良好的亲和力,GSE23160芯片验证预测DRD2、GSK3β和NR3C1具有差异性(P<0.05)。结论基于网络药理学及分子对接和基因芯片验证了右美托咪定通过多靶点、多生物学功能、多通路干预脑缺血再灌注损伤,并验证DRD2、GSK3β、NR3C1可能是核心基因,预测关键诊断基因和潜在治疗基因,为进一步研究奠定坚实基础。

Objective To analyze the mechanism of dexmedetomidine in treatment of cerebral ischemia-reperfusion injury based on bioinformatics,and to identify the hub genes by molecular docking and gene expression omnibus(GEO)chip verification.Methods PubChem and GeneCards were used to screen the intersection targets of dexmedetomidine and cerebral ischemia-reperfusion injury,establish a PPI network to determine hub genes,and perform GO and KEGG enrichment analysis.Finally,the Hub genes were verified by molecular docking and GEO chip data.Results There were 43 intersection targets between dexmedetomidine and cerebral ischemia-reperfusion injury.PPI screening obtained a topological network with 41 nodes and 103 edges,and the Hub genes were HTR2A,OPRM1,DRD2,SLC6A4,GRM5,CYP2C19,SLC6A3,NR3C1,and GSK3β.GO and KEGG analysis showed that dexmedetomidine intervention of cerebral ischemia-reperfusion injury involved 254 biological functions and 58 signaling pathways.Molecular docking verified that the hub genes had good affinity,and GSE23160 chip verified that DRD2,GSK3β,and NR3C1 were different(P<0.05).Conclusions Based on network pharmacology,molecular docking,and gene chip,this study found that dexmedetomidine intervention of cerebral ischemia-reperfusion injury through multi-targets,multi-biological functions and multipathways,verified that DRD2,GSK3β,and NR3C1 may be the hub genes,predicted key diagnostic genes and potential therapeutic genes,and laid a solid foundation for further research.